There are limited treatment options for patients with advanced cancer. Current therapies include surgery, chemotherapy, and radiation therapy. These treatments are relatively ineffective and have considerable morbidity associated with them. An alternative treatment strategy that has been successful for many melanoma and renal cell carcinoma patients is immunotherapy. So far, immunotherapy has not been well tested in breast and ovarian cancer patients. The major factors which have limited the development of immunotherapy for most cancers is there are the lack of T cell antigens expressed by cancer cells and that the antigens identified so far are poorly immunogenic. One antigen that has been extensively studied as a potential target for immunotherapy for many cancers is the proto-oncogene Her-2/neu. Several groups have reported isolating Her-2/neu reactive T cells that recognize a variety of cancers including breast, colon, and ovarian cancer. However, early clinical trials in patients vaccinated with antigenic Her-2/neu peptides failed to elicit an effective anti-tumor immune response. Since most immunotherapy strategies are totally dependent on boosting the host anti-tumor immune response, attempts to boost the anti-tumor immune response to weakly immunogenic antigens expressed by cancer cells such as Her-2/neu have proven to be ineffective against breast, ovarian, lung, and colon cancer. We have developed an alternative strategy for providing antitumor reactivity to cancer patients which does not require boosting the host anti-tumor immune response. Using retroviral vectors encoding T cell receptor (TCR) genes, we have been able to transfer the specificity of tumor reactive T cell clones to normal peripheral blood T cells. The goal of this proposal is to determine if normal peripheral blood T cells can be engineered to recognize Her-2/neu+ breast, ovarian, lung, and colon cancer cells and to evaluate therapeutic the efficacy of TCR transduced T cells in treating established Her- 2/neu+ tumors in mice. Successful completion of these goals may lead to a new treatment for cancer patients with Her-2/neu+ tumors using autologous TCR gene modified T cells. [unreadable] [unreadable]